Obesity now affecting one in five children in the U.S. and gestational diabetes (GDM) increasing among all racial and ethnic groups, it is becoming increasing important to understand how events that happen early in life, even before birth, can alter the obesity trajectory of individuals. The fetal over-nutrition hypothesis posits that intrauterine environment of diabetic and obese pregnancies may permanently alter the offspring's long- term risk for obesity and metabolic diseases, through developmental programming. Although several epidemiologic studies have provided evidence in support of this hypothesis there are many unanswered questions, including the biologic mechanisms responsible for these effects, and the relative contribution of the postnatal environment. The EPOCH (Exploring Perinatal Outcomes in CHildren) Study, a retrospective cohort study completing it's first five year grant cycle, is proposing to address some of these questions. EPOCH participants were 604 children (and their mothers) aged 6-13 years in 2006-2010, who were offspring of singleton pregnancies. The mother-child pairs were members of the Kaiser Permanente of Colorado Health plan (KPCO) at birth (B) and at first EPOCH visit (T1). EPOCH findings provided novel evidence that fetal over- nutrition is operating among contemporary US children, and possible avenues for prevention. EPOCH offspring are now entering puberty, another critical developmental period, associated with rapid growth, alterations in fat patterning, and development of insulin resistance. The goal of this renewal of RO1 DK068001-6 is to continue to follow this cohort for another five years, when participating youth will be 12-19 years (T2) to determine if the detrimental effects conferred by intrauterine over-nutrition become more evident during transition through puberty. The specific aims for this follow-up period are: Aim1: Follow the EPOCH cohort of youth exposed and not exposed to GDM in utero to explore the effects of fetal over-nutrition on: a) childhood growth, development and distribution of adiposity; b) cardiovascular (CV) risk factors; and c) metabolic abnormalities that are precursorsof type 2 diabetes (T2D), among 12-19 year old youth. Explore how postnatal feeding patterns (breastfeeding, high energy, high saturated fat intake) influence these associations. Aim No. 2. To explore the hypothesis of defective leptin signaling through which fetal over-nutrition could increase the risk of obesity in children. Aim 3: To examine the epigenetic DNA methylation profiles (using offspring DNA collected at T1) in specific genes according to fetal exposure status and assess whether DNA methylation profiles mediate the association between exposure to maternal GDM in utero and childhood outcomes. PUBLIC HEALTH RELEVANCE: The fetal over-nutrition pathway to obesity may lead to a trans-generational vicious cycle explaining at least in part the increases in obesity, and type 2 diabetes seen over the past several decades. The EPOCH study will explore how and when prenatal over-nutrition leads to the development of childhood obesity, whether windows of opportunity for prevention may exist, and what the likely avenues for prevention may be. EPOCH is ideally positioned to answer some of these questions in a contemporary cohort of well-characterized U.S. youth whose prenatal exposures have been directly assessed and who have longitudinal outcome measures carefully collected from birth, and as these youth transition through puberty. Identifying the answers to some of these questions represents the first step towards reducing the epidemic of pediatric obesity and type 2 diabetes.